tbuckley/cabot-search huggingface dataset:
Impact of adjuvant immunotherapy in resected stage II/III/IV melanoma: A single center experience.
Authors: Alberto Rafael Sevillano Tripero, Carolina Ortiz, Julia Lostes, Domingo Bodet, Carla Ferrandiz, Patricia Bassas, Paula Chiquillo, Guillermo Villacampa, Kreina Sharela Vega-Cano, Vicente García-Patos, Juan Recio, Eva Muñoz-Couselo
Journal: Journal of Clinical Oncology (2023)

e21565 Background: The incidence of malignant melanoma (MM) in Mediterranean countries is estimated at 3- 5/100.000 inhabitants/year with a predicted rising trend. MM is responsible for over 90% skin cancer deaths due to its tendency to metastasize early. Surgical excision is the treatment of choice for early-stage melanoma, however, 40-60% of patients with high recurrence risk melanoma, thick ulcerated primary melanomas (Stage IIC) and those with lymph node involvement (Stage III), experience a tumor relapse. Adjuvant therapy in resected high-risk melanomas has shown improved Relapse-Free-Survival (RFS), although no Overall Survival (OS) benefit has been observed to date. This retrospective observational study, conducted in one center, aims to evaluate effectiveness and safety of adjuvant therapies for resected high-risk melanoma. Methods: Single center cross-sectional study that included patients with a resected high-risk melanoma candidate for adjuvant treatment, at 2015-2022 period. Convenience sampling 48 patients recruited. Median follow up 55,4 months. Results: Median age was 54y, 52% were male and 93’6 is cutaneous melanoma. 53% were BRAF WT. Median Breslow (mm) was 3’85, median num/mm2 mitosis are 4 and 62’5% had ulceration. 15% presented satelosis or intransit metastasis and 55% had a lymphadenectomy. Melanoma stage: 9%IIB, 11%IIC, 11%IIIA, 25%IIIB, 38%IIIC, 2% IIID and 2% IV. Adjuvant treatment: 22% nivolumab, 20% ipilimumab+nivolumab, 12% ipilimumab, 16% interferon.75% of patients completed adjuvant treatment, 14% stopped for toxicity and 9% presented disease relapse (21% loca, 64% systemic). Best treatment response in relapse was 12% partial response, 37% progression. Toxicity: 18% presented grad ¾ toxicity. Efficacy: median RFS was 78’8m and median OS was NR. Conclusions: Adjuvant treatment is associated with an increased DFI in resected high risk melanoma patients. Adjuvant therapy was generally well tolerated, with manageable adverse events, consistent in type and incidence to those seen in clinical trials that allowed the approval for these compounds in adjuvant and metastatic scenarios. Prospective studies are needed to determine new biomarkers for the selection of those patients who could benefit to a greater extent from adjuvant therapies in resected high-risk melanoma.
Comparison of gene alterations detected with tumor tissue and plasma in a Chinese population with advanced lung adenocarcinoma.
Authors: Yong Zhang, Si Li, Wenjing Xi, Chan Zhu, Yunjie Song, Wanglong Deng, Chuang Qi
Journal: Journal of Clinical Oncology (2023)

e20511 Background: Currently, plasma cell-free DNA has been recommended as an alternative biomarker for guiding precision treatment in lung cancer. In this study, we retrospectively reviewed gene alterations detected by matched plasma and tumor tissue to investigate the concordance and sample-specific observations. Methods: The inclusion criterions included 1) samples collected between January and October 2022, 2) clinical stage IV, lung adenocarcinoma, 3) plasma taken within 4 weeks of tumor biopsy, 4) cell-free DNA and tumor DNA were extracted for next-generation sequencing (sequencing depth, 4000X for tissue and 10000X for plasma), with a pan-cancer 539-gene panel in a CAP-certificated laboratory. Alterations including mutations (SNV, indel), fusion and CNV of driver genes, including EGFR, ALK, ROS1, RET, MET, NTRK, BRAF, ERBB2, KRAS (9-gene), were emphatically reviewed and compared. Concordance was defined as tissue and plasma reported alterations within the same gene, or both negative. Tumor mutation burden (TMB) was calculated as ratio between total number of non-synonymous variants and total size of coding region. Results: After reviewing 630 patients with matched plasma and tumor samples, 121 patients diagnosed with stage IV lung adenocarcinoma were included. The top five altered genes in tissue were TP53 (71.07%), EGFR (57.86%), MYC (33.88%), MUC16 (23.97%), CDK6(23.97%), those in plasma were TP53 (52.89%), EGFR (40.5%), DNMT3A (28.93%%), MUC16 (18.18%), LRP1B (15.7%). The detection rates of driver gene (9-gene) alterations were 92.56% (112/121) for tissue and 69.42% (84/121) for plasma. The overall concordance of 9-gene alteration was 69.42%, it increased to 74.38% excluding fusions and CNVs. Among mutations, EGFR (61/121), KRAS (14/121), ERBB2 (9/121) and BRAF (3/121) were more often reported in tissue or plasma. The concordances were 71.13% ( EGFR), 66.67% ( BRAF), 55.56% ( ERBB2) and 42.86% ( KRAS) respectively. We also observed five mutations ( EGFR G719A/S768I, KRAS G12A/Q61L/A146P) that were only detected in plasma in four patients. One patient was detected with STRN-ALK only in plasma. These plasma-only mutations might provide extra efficacy predicting (sensitive or resistance) for EGFR/KRAS/ALK inhibitors. TMB of plasma and tissue showed strong correlation (Pearson’s Correlation Coefficient of 0.74). 14 and 13 patients were divided into TMB-H ( &gt; 10 mutations/Mb) in tissue and plasma respectively, the concordance rate was 94.21% (114/121). Among qualified samples for MSI evaluations, non MSI-H was detected, the concordance rate was 100%. Conclusions: The sequencing results of matched plasma and tissue presented good concordance of driver gene alterations (especially for EGFR mutations), TMB-H and MSI-H. These suggested ctDNA testing might be a reliable commentary approach to tissue to guide target and immunotherapy in advanced lung adenocarcinoma.
An exploratory analysis of lung cancer survival using NGS genetic predictors and partial least squares.
Authors: Silvia Sequero-Lopez, Francisco Jesus Martinez-Murcia, Diego Castillo-Barnes, Javier Moreno-Garcia, Ana Segura-Perez, Nicolas Gallego-Molina, Andres Ortiz, Javier Ramirez
Journal: Journal of Clinical Oncology (2023)

e21007 Background: According to the IARC, lung cancer is one of the most common types of cancer worldwide (2.09 million of cases in 2018). Some genetic alterations (ALK, ROS1, EGFR, etc.) are known to play a key role in its origin. Fortunately, target therapies have been developed in the last years increasing patients Overall Survival (OS). Methods: Next-Generation Sequencing (NGS) is a powerful tool to determine which specific mutations occur in these genes. Nevertheless, despite some of them have been labeled as pathogenic, we still do not know exactly their effect on the OS. In this context, we have evaluated the NGS (Ion Torrent™ S5, kit Oncomine™ Focus Assay, Oncomine Focus-520- W3.0-DNA v5.14) results of 119 patients diagnosed with lung adenocarcinoma (89 variants in 28 genes) with a cross-validated (k = 5) schema using Partial Least Squares (PLS) and multiple repetitions to determine the coefficient variability from the genetic alterations modeling the OS. This gives us a measure of the proportion of variance in the OS (dependent variable) that is explained by the mutations (independent variables) in our statistical model. Results: Analyzing our results, alterations on ALK EML4-ALK V1 (CI -58.7 to -18.8); BRAF SNV exon15 p.Val600Glu (CI -66.1 to 0.0); CTNNB1 SNV exon3 p.Thr41Ala (CI -84.3 to 8.8) and p.Thr41Ile (CI -26.0 to 0.6); EGFR CNV (CI -68.5 to -5.1) and DEL exon19 p.Glu746-Ala750 (CI -66.9 to 16.4); KRAS SNV exon2 p.Gly12Val (CI -76.1 to -39.3) and p.Gly13Cys (CI -66.0 to -36,9); MET CNV (CI -50.0 to 1.3) and FUS exon13 to exon15 (CI -46.8 to 33.6); and PIK3CA SNV exon10 p.Glu545Lys (CI -99.0 to -35.6) have a negative impact on the OS. In contrast, mutations in CTNNB1 SNV exon3 p.Ser37Phe (CI -26.3 to 105.5); EGFR SNV exon21 p.Leu858Arg (CI -32.7 to 121.3); KRAS SNV exon2 p.Gly12Ala (CI 1.3 to 39.3); KRAS SNV exon3 p.Gln61His (CI -53.32,50,11) lead to a better prognosis on OS. Note that our analysis involved patients not treated due to their tumoral progression: CTNNB1 SNV exon3 p.Thr41Ile (1); EGFR SNV exon21 p.Leu858Arg (3); CTNNB1 SNV exon3 p.Thr41Ala (1); PIK3CA SNV exon10 p.Glu545Lys (1); ALK EML4-ALK V1 (1) and KRAS SNV exon2 p.Gly12Val (1). Conclusions: Though alterations in the EGFR and ALK genes usually present a favorable prognosis, our work suggests that some of their variants are associated with a poor survival. This study also reveals other mutations like alterations on PIK3CA and CTNNB1 genes, which may impact lung cancer prognosis and will require further exploration.
Physical therapy and rehabilitation for improvement of quality of life of breast cancer patients.
Authors: Mariam Abuladze, Tamar Esakia, Tamar Melkadze, Elene Mariamidze, Nana Otkhozoria, Sofia Tsitsilashvili, Margarita Katcharava, Nikoloz Chokoshvili, Tamta Cholikidze, Davit Barabadze, Bakar Tchatchiashvili, Khatuna Saganelidze
Journal: Journal of Clinical Oncology (2023)

e18711 Background: One of the most critical factors that cancer patients need to consider when it comes to their rehabilitation is the availability of effective and personalized rehabilitation programs. Aside from being a vital part of cancer rehabilitation, exercise can also improve the quality of life for cancer patients and help them maintain a healthy and balanced lifestyle. The purpose of this study is to adapt an evidence-based exercise program and rehabilitation techniques for breast cancer patients undergoing adjuvant chemotherapy and test the efficacy of this approach combining physical therapy, massage therapy, equine therapy (intervention group) compared to chemotherapy only (control group) for improving quality of life. Methods: This is two-armed, randomized controlled trial to test the efficacy of physical therapy and rehabilitation for improving quality of life of breast cancer patients undergoing adjuvant chemotherapy. The intervention program included physical therapy, massage therapy, equine therapy. Control group received standard care, treatment group received standard care plus intervention. All patients completed the quality of life questionnaire (EORTC-QLQ-C30) at baseline and at 4 months. All participants randomized to treatment group first received one-on-one consultation with oncologist, Physical Medicine and Rehabilitation (PM&amp;R) physicians and physical therapists. The intervention components include tri-weekly program that included physical therapy, massage therapy and equine therapy. Statistical methods (STATA) were used to analyze the data. We began data analyzes with observational statistics and independent variable analyzes. Results: Even though we did not find any difference in some aspects of intervention group during observational study, we saw a significant difference in DID model which showed significant improvement in data. Compared to control group, intervention group showed improved Quality of life (43.57***), improved PF (48.76***), RF (53.3***), EF (56***), CF (37.66**) and SF (52.85***). Another important observation is a fact that age and stage of the disease had no effect on quality of life or affected any aspect of this study, reasons of which has to be further analyzed. Conclusions: Our study proved that physical therapy and rehabilitation can be useful in improving the quality of life of breast cancer patients undergoing chemotherapy.
Updated OS of patients with AL amyloidosis after CAEL-101.
Authors: Michael Sang Hughes, Samuel M Pan, Rajshekhar Chakraborty, Jayant Raikhelkar, Mathew Maurer, Markus Y. Mapara, Andrew Eisenberger, Suzanne Lentzsch, Divaya Bhutani
Journal: Journal of Clinical Oncology (2023)

8026 Background: Morbidity and mortality remain high in immunoglobulin light chain (AL) amyloidosis due to organ involvement despite hematologic remission. Few anti-amyloid fibril therapies for AL amyloidosis exist. We previously published the results of the phase 1a/1b study of CAEL-101 in AL amyloidosis showing significant improvement in organ response rates. 1 We report long-term outcomes. Methods: Patients enrolled in NCT02245867 with relapsed/refractory AL amyloidosis received in phase 1a, a one-time dose-finding CAEL-101 infusion and in phase 1b, 4 weekly CAEL-101 infusions with preplanned dose escalation. Patients were evaluated for organ response for 12 weeks after last infusion. We extracted clinical, laboratory, and pathology data regarding clinical course beyond 12 weeks after last treatment. We performed a review of all AL amyloidosis patients at our center not treated with CAEL-101 1/01/2012-12/30/19 as clinical comparisons. Results: 22 patients were enrolled in CAEL-101. 5 patients were treated in both phase 1a and phase 1b. With median follow-up of 81.3 months (IQR 60.4-87.7), long term follow-up data are available for 19/22 patients. 5 patients died during long term follow-up: 3 from progressive AL amyloidosis; 1 from organ transplantation complication; and 1 from venous thromboembolism sequelae. Among patients with organ data available, 10/17 had hematologic progression and received next line therapy. 5/17 patients had organ progression. All patients with organ PD had previous/concomitant hematologic PD. Median OS was not reached; median organ PFS was 93.3 months (38.9-NR). No delayed adverse events occurred. Comparison with historical control groups revealed trends toward improved OS: HR 0.42 (0.09-1.81 p=0.23) in all comers AL amyloid controls, and HR 0.20 (0.03-1.16 p=0.07) in cardiac controls. Kaplan-Meier analysis and Cox regression were performed. Conclusions: Patients with relapsed/refractory AL amyloidosis who received a low cumulative amount of the novel anti-amyloid CAEL-101 in a phase 1a/1b study had lengthy overall and progression-free survival compared to historical controls. Patterns of organ progression after initial response may reflect intrinsic differences in organ vulnerability. The CAEL101-301 and CAEL101-302 phase 3 clinical trials are underway to confirm these findings. Reference: 1. Edwards CV, Rao N, Bhutani D, et al: Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. Blood 138:2632-2641, 2021. [Table: see text]
Tumor immune microenvironment of different lesions in patients with multiple primary lung cancer.
Authors: Yun Li, Yingxue Qi, Ningning Luo, Mengmeng Li, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2023)

e20549 Background: More and more multiple primary lung cancers (MPLCs) are found clinically. The driver genes and clinical differences between different lesions in MPLCs are obvious, which may affect the choice of subsequent treatment options. As a new type of therapy, immunotherapy has improved the survival of lung cancer patients to a certain extent. However, the efficacy of immunotherapy on different lesions of the same patient with MPLCs is not yet clear. Our study explored the similarities and differences of the tumor immune microenvironment in MPLCs lesions and provided a theoretical basis for immunotherapy in MPLCs. Methods: We collected 20 surgical tumor lesion samples from 10 patients with MPLCs for 289-gene panel RNA sequencing using NanoString nCounter. All tumor tumor immune microenvironment (TIME) cell infiltration scores were calculated as arithmetic mean of the constituent genes. Immune infiltration and expression of immune-related genes in different groups were assessed. Results: All 10 patients in our study were lung adenocarcinoma. Firstly, we classified them using an unsupervised consensus clustering based on TIME-signature gene expression used nonnegative matrix factorization of R package. The results revealed the cluster number of two was optimal (TIME Cluster1: n = 6 patients / 12 lesions; TIME Cluster2: n = 4 patients / 8 lesions). It is worth noting that the two lesions of the same patient are divided into the same group, indicating that the immune microenvironment status of the two lesions of the same person is basically similar. In addition, the nertrophils, NK CD56dim cells and GEP score of Cluster1 is significantly higher than that of Cluster2. Then we grouped them according to gender, ipsilateral or heteroside primary lesions, left or right lung, and pathological infiltration or non-infiltration, and found there was no significant difference in the immune microenvironment between the all the two groups. Conclusions: Dual primary samples from the same individual have similar immune microenvironments and may respond similarly to immunotherapy. Prospective immune-related clinical trials can be designed for further verification in MPLCs patients.
Mortality benefit of a blood-based biomarker panel for lung cancer and the PLCO cohort.
Authors: Johannes Fahrmann, Ehsan Irajizad, Edwin J. Ostrin, Jody Vykoukal, Jennifer Dennison, James Patrick Long, Kim-Anh Do, Ziding Feng, Samir M Hanash, Tracey Marsh
Journal: Journal of Clinical Oncology (2023)

8560 Background: A 4-protein biomarker panel (4MP) combined with the validated PLCO m2012 clinical risk model has been shown to improve lung cancer risk estimation over either metric alone. We investigated whether these panels in combination could also identify individuals at high risk of harboring a lethal lung cancer. Methods: We used data from an established logistic regression combining the 4MP and the PLCO m2012 risk model, which were assessed in pre-diagnostic sera from 552 lung cancer cases and 2,193 non-cases from the Prostate Lung Colorectal and Ovarian (PLCO) cohort. Of the 552 lung cancer cases, 387 (70%) died from lung cancer. Cumulative incidence of lung cancer death as well as sub-distributional and cause-specific hazard ratios were calculated based on 4MP+PLCO m2012 risk scores at a pre-defined 1.0% and 1.7% 6-year risk thresholds, which correspond to the 2013 and 2021 US Preventive Services Task Force lung cancer screening criteria, respectively. Results: When considering cases diagnosed within 1 year of blood draw and all non-cases, the AUC estimate of the 4MP+PLCO m2012 model for risk prediction of lung cancer death was 0.88 (95% CI: 0.86-0.90). Among cases, the cumulative incidence of lung cancer death was statistically significantly higher in individuals with 4MP+PLCO m2012 scores above the 1.0% 6-year risk threshold (modified χ 2 : 5.42, P: 0.02). Corresponding sub-distributional and lung cancer death-specific hazard ratios for test-positive cases were 1.69 (95% CI: 1.07-2.66) and 1.80 (95% CI: 1.15-2.82), respectively. Conclusions: The blood-based biomarker panel in combination with PLCO m2012 identifies individuals at high risk of a lethal lung cancer.
Concurrent durvalumab plus chemoradiation therapy followed by durvalumab in Chinese patients with unresectable stage III non-small cell lung cancer: CRUISER study.
Authors: Feifei Teng, Hong Ge, Buhai Wang, Yaping Xu, Xue Meng, Suzhen Wang, Ligang Xing, Jinming Yu
Journal: Journal of Clinical Oncology (2023)

e20576 Background: Concurrent chemoradiation therapy (CRT) followed by durvalumab consolidation therapy has demonstrated significant survival benefit for unresectable stage III non-small cell lung cancer (NSCLC) in PACIFIC trial. However, there are still 20%-30% patients who have disease progression (PD) or intolerable toxicity. This prospective study aimed to evaluate safety and clinical activity of concurrent durvalumab plus CRT followed by durvalumab in unresectable stage III NSCLC (NCT04982549). Methods: This is a single-arm, open-label, multicenter phase II clinical trial and planned to enroll 35 patients with unresectable stage III NSCLC of any PD-L1 expression level and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. All of patients will receive concurrent durvalumab 1500mg every 4 weeks plus SoC CRT followed by durvalumab monotherapy 1500mg every 4 weeks until PD or unacceptable toxicity. One cycle of induction durvalumab plus chemotherapy is allowed before radiotherapy upon investigator discretion. The primary endpoint is the incidence of grade ≥3 immune-mediated adverse event (AE). Here we report the preliminary clinical activity and safety of a preplanned interim analysis of this study. Results: By September 2022, 28 patients finished concurrent durvalumab plus CRT treatment and were included for analysis. 21 (75%) of 28 patients had radiographic tumor evaluation and entered the consolidation treatment stage, 7 (25%) patients discontinued treatment without radiographic tumor evaluation because of intolerable AE (5 patients) or withdrawing from the study (2 patients). 20 (71.4%) of 28 patients received one cycle induction therapy of durvalumab plus chemotherapy. The median age of these 28 patients was 64 years old, 26 (92.9%) of 28 patients with ECOG performance status of 1, and 14 (50%) of 28 patients were squamous carcinoma. Disease stage was IIIA (42.9%, 12/28), IIIB (39.3%, 11/28) and IIIC (17.9%, 5/28), with most of them (89.3%, 25/28) had N2/N3 lymphatic metastasis. 19 (90.5%) of 21 patients achieved objective response. Median interval from enrollment to the first radiological evaluation was 112 days. Grade ≥3 treatment-related adverse event (TRAEs) occurred in 13(46.4%) of 28 patients, including six (21.4%) possibly related to durvalumab. Conclusions: The interim results from CRUISER study showed promising clinical activity and manageable toxicity of durvalumab plus concurrent CRT followed by durvalumab for unresectable stage III NSCLC. The survival outcome and biomarker exploration will be analyzed upon data maturity. Phase 3 PACIFIC-2 study investigating clinical outcome of concurrent durvalumab plus CRT in unresectable NSCLC is ongoing. Clinical trial information: NCT04982549 .